Sulfaquinoxaline (SQX) has been detected in environmental water samples, where its side effects are still unknown. To the best of our knowledge, its oxidation by Fenton and photo-Fenton processes has not been previously reported. In this study, SQX oxidation, mineralization, and toxicity (Escherichia coli and Staphylococcus aureus bacteria) were evaluated at two different setups: laboratory bench (2 L) and pilot plant (15 L). The experimental design was used to assess the influence of the presence or absence of radiation source, as well as different H2 O2 concentrations (94.1 to 261.9 mg L−1). The experimental conditions of both setups were: SQX = 25 mg L−1, Fe(II) = 10 mg L−1, pH 2.8 ± 0.1. Fenton and photo-Fenton were suitable for SQX oxidation and experiments resulted in higher SQX mineralization than reported in the literature. For both setups, the best process was the photo-Fenton (178.0 mg L−1 H2 O2), for which over 90% of SQX was removed, over 50% mineralization, and bacterial growth inhibition less than 13%. In both set-ups, the presence or absence of radiation was equally important for sulfaquinoxaline oxidation; however, the degradation rates at the pilot plant were between two to four times higher than the obtained at the laboratory bench.